Malaria causes more than 500 million clinical cases and one-million deaths per year. Plasmodium falciparum is responsible for most malaria-related deaths. Anti-malarial drugs save millions of lives every year;however, the evolution of drug resistance in P. falciparum is a major global health threat. We will investigate the dynamics of mutations associated with chloroquine and sulfadoxine-pyrimethamine (SP) resistance across multiple P. falciparum populations with different epidemiological characteristics and demographic histories. Overall, this proposal aims to generate new empirical and theoretical knowledge about how advantageous mutations can sweep through large structured populations with complex demographic histories and then decline when the selective pressure changes. By comparing several populations, we will provide information regarding which types of populations are most prone to the emergence of drug resistance or to the reemergence of drug sensitivity and will provide theoretical tools to evaluate potential drug policies (e.g. combination therapy or drug rotation) under scenarios likely to be encountered in different endemic areas. (1) We will use microsatellites linked to drug resistance alleles and neutral loci to estimate the relative fitness of mutations associated with resistance in the context of the parasite population demography (e.g. local population structure, effective population size, and amount of recombination) during single and/or multiple selective sweeps. We will (1A) estimate the demographic history of P. falciparum populations using neutral markers from seven endemic areas: two from South America, four from Africa, and one from Asia;(1B) assess how the demographic history of these populations affects the fitness of mutations associated with SP and chloroquine resistance sweeping simultaneously in a population in the presence of drug pressure;1C) estimate the fitness cost of resistance in the absence of drug pressure. (2) We will develop mathematical models that predict/assess the dynamics of resistant and sensitive alleles taking into account their relative fitness, the disease ecology, and the demographic history of the parasite population. 2A) We will validate them by (i) predicting patterns of selective sweeps and linkage disequilibrium on loci under selection by antimalarial drugs in specific populations, (ii) testing the hypothesis that drug-resistance is more likely to emerge under low transmission conditions like those observed in South America and Southeast Asia, and (iii) testing the hypothesis that in the absence of drug pressure, drug sensitivity is more likely to re-emerge under high transmission conditions like those in Africa.